Inflammatory bowel disease is a collective name of ulcerative colitis and Crohn's disease. Ulcerative colitis is a non-specific chronic inflammatory disease in which mucosal damage in large intestine diffusely and continuously ascends from rectum. On the other hand, in Crohn's disease, inflammation is observed at various sites in gastrointestinal tract, and transmural conditions such as deep ulcer and perforation are observed. Although the pathogenesis of these diseases is not known, various causes such as infections, environmental factors, psychosomatic medical problems, inheritance and immune abnormality are assumed, and the diseases are generally thought to be multiple-cause diseases caused by being complexly intertwined with the above-described factors.
The major symptoms of ulcerative colitis are mucous and bloody stool, abdominal pain and diarrhea, and anemia and tachycardia are observed depending on the degree of bleeding. Inappetence, weight loss, general malaise and easy fatigability are also observed in some cases. Complications in intestinal tract include massive bleeding, perforation, toxic megacolon and occurrence of colon cancer. Complications in organs other than intestinal tract include skin diseases such as erythema nodosum and pyoderma, ophthalmic diseases such as conjunctivitis and iridocyclitis, and stomatitis, and primary sclerosing cholangitis is rarely observed.
The most frequent symptoms of Crohn's disease are diarrhea and abdominal pain. Further, fever, melena, weight loss due to impaired absorption, general malaise, anal pain and anemia are often observed. Complications in intestinal tract include constriction, fistula and adhesion. Complications in organs other than intestinal tract include skin diseases such as necrotic pyoderma and erythema nodosum, joint disease, stomatitis, cholangitis and fatty liver. Crohn's disease is classified into small intestinal type, small and large intestinal type and large intestinal type.
Peak of onset of inflammatory bowel disease is in twenties, and recurrence and remission are easy to be repeated, so that frequently, QOL is seriously disturbed. Further, since the number of patients is increasing due to the recent changes of environmental factors such as the change in dietary life, the importance of therapy of inflammatory bowel disease is increasing year by year.
Therapy for inflammatory bowel disease is performed by means of pharmacotherapy, apheresis or surgical therapy. Pharmacotherapy includes the remission-induction therapy in which the symptoms are alleviated and remission is quickly induced, and the prophylactic remission-maintenance therapy in which the remission period is prolonged. In the remission-induction, in cases where the symptoms are slight or moderate, the therapy is based on oral administration of salazosulfapyridine or 5-aminosalicylic acid. These drugs are also used for the prophylactic remission-maintenance therapy. If the effects of the drugs are insufficient or the symptoms are more serious, adrenocortical steroids or immunosuppressive agents are used.
Therapy for Crohn's disease is mainly performed by means of nutritional therapy, pharmacotherapy or surgical treatment. The pharmacotherapy is based on 5-aminosalicylic acid preparation, and adrenocortical steroids or immunosuppressive agents are used depending on the symptoms.
Recently, it has been proved that local cytokines strongly participate in the pathogenesis of inflammatory bowel disease, and studies on the drugs targeting the cytokines are underway. Anti-TNF-α antibody therapy targeting TNF-α, which is a key cytokine of Crohn's disease, is presently used for the amelioration of the lesion or for decreasing the amount of steroids.
However, known therapeutic agents for inflammatory bowel disease does not sufficiently satisfy the needs of users with respect to the purpose such as amelioration of symptoms or reduction of side effects.
It is known that leukocytes strongly participate in the development of inflammatory bowel disease. In recent years, a number of trials for inhibiting the development of the disease are underway using monoclonal antibodies, antisenses or low molecular compounds which inhibit the activation or hyperfunction of leukocytes, or which inhibit the proinflammatory substance produced by leukocytes. Examples of the target molecules include CD4 which is a surface molecule expressed on leukocytes, adhesive molecules, regulatory molecules of T cell activation (CD40L, CD28 and CTLA-4), phosphorylation signals of leukocytes, transcription factors, various inflammatory chemical mediators such as inflammatory cytokines and LTB4, active oxygen and various enzymes (PDEIV, lipoxygenase and the like). The therapeutic effects by inhibiting these molecules on inflammatory bowel disease have been proved by using monoclonal antibodies or low molecular inhibitors in human clinical studies or in experimental animal models (see, for example, Non-patent Literature 1, Non-patent Literature 2 and Non-patent Literature 3).
In the lesion tissues in inflammatory bowel disease, prominent infiltration of leukocytes is observed. It is widely recognized that the infiltration is due to the leukocytes normally circulating in the blood which penetrate the vascular wall, resulting in gathering of the leukocytes at the lesion tissues. It has been proved that infiltration of the leukocytes via vascular endothelium is caused by the interaction between integrins on the leukocytes and adhesion molecules which belong to the immunoglobulin family such as ICAM-1 and VCAM-1 on the vascular endothelial cells.
Intercellular adhesion molecule-1 (ICAM-1: CD54) is an adhesion molecule belonging to the immunoglobulin super family, and mainly exists on vascular endothelium. ICAM-1 binds to lymphocyte function associated antigen-1 (LFA-1: integrin α Lβ2, CD11a/CD18) and Mac-1 (integrin αMβ2, CD11b/CD18) on leukocytes, and is involved in extravasation of inflammatory cells (see, for example, Non-patent Literature 4). Existence of vascular cell adhesion molecule-1 (VCAM-1) also has been confirmed in intestinal mucosal tissues (see, for example, Non-patent Literature 5), and the molecule is involved in extravasation of leukocytes by binding to very late activating antigen-4 (VLA-4: integrin α4β1)(see, for example, Non-patent Literature 6). Further, as an adhesion molecule specific to the endothelial cells in gut-associated lymphoid tissues, mucosal addressing cell adhesion molecule-1 (MAdCAM-1) is known. MAdCAM-1 binds to lymphocyte Peyer's patch HEV adhesion molecule-1 (LPAM-1: integrin α4β7), and plays an important role in gut immunity (see, for example, Non-patent Literature 7 and Non-patent Literature 8). It is also known that integrin α4β7 binds to VCAM-1 similar to integrin α4β1 (see, for example, Non-patent Literature 9). The therapeutic effects on inflammatory bowel disease by inhibiting the binding between the adhesion molecules and their integrin receptors have been proved by using antisenses to ICAM-1 or monoclonal antibodies to integrin α4 in human clinical studies (see, for example, Non-patent Literature 10) or in experimental animal models (see, for example, Non-patent Literature 11, Non-patent Literature 12 and Non-patent Literature 13).
As for the technology, a therapeutic agent for inflammatory bowel disease, which has the above-described mechanism, is disclosed in Patent Literature 1. However, in the publication, the compounds having the structure claimed in our disclosure are not described. Use of the compounds having the structure claimed in our disclosure as a bone resorption inhibitor is described in Patent Literature 2. However, the compounds having the structure claimed in our disclosure are not concretely described therein at all.    Patent Literature 1: WO 99/26923    Patent Literature 2: WO 95/32710    Non-patent Literature 1: Rev. Gastroenterol Disord., 4, 66 (2004)    Non-patent Literature 2: Arch. Pharmacal. Res., 22, 354 (1999)    Non-patent Literature 3: Trends. Pharmacol. Sci. 25, 430, (2004)    Non-patent Literature 4: Annu Rev Immunol., 11, 767 (1993)    Non-patent Literature 5: Gut., 36, 724 (1995)    Non-patent Literature 6: Res. Immunol., 144, 723 (1993)    Non-patent Literature 7: Adv. Immunol., 72, 325 (1999)    Non-patent Literature 8: Am. J. Phathol., 151, 97 (1997)    Non-patent Literature 9: J. Immunol., 151, 2471 (1993)    Non-patent Literature 10: Inflammatory Bowel Disease, 8, 291 (2002)    Non-patent Literature 11: J. Clin. Invest., 92, 372 (1993)    Non-patent Literature 12: J. Immunol., 151, 4790 (1993)    Non-patent Literature 13: Gastroenterology, 111, 1373 (1996)